ABSTRACT
Platelet hyperactivity plays a critical role for initiating several vascular diseases such as atherothrombosis. Therefore, development of effective antiplatelet agents is necessary for ameliorating platelet-related diseases. In this study, we investigated the effects of the new synthesized compound, MP407 on platelet aggregation and further elucidated the underlying mechanisms. Our results demonstrated that MP407 dose-dependently inhibited collagen-induced platelet aggregation, thromboxane B2 (TXB2) production, intracellular Ca2+ mobilization, platelet membrane GPIIb/IIIa expression, and the phosphorylation of Akt, GSK3ß, p38MAPK, and phospho (Ser) PKC substrate (p47). Moreover, MP407 is able to increase the cyclic AMP formation both in resting and activated platelets. However, blocking cyclic AMP formation with 2'5'-ddAdo, an inhibitor of adenylate cyclase, greatly reversed the antiplatelet activity of MP407 and related platelet-activating pathways. MP407 also enhanced VASP phosphorylation at Ser157 in collagen-stimulated platelets, which was attenuated by addition of 2'5'-ddAdo. Therefore, the antiplatelet activity of MP407 may be modulated by cyclic AMP-dependent regulation of Akt, GSK3ß, p38MAPK and VASP phosphorylation. Notably, treatment with MP407 markedly reduced the pulmonary thrombosis and the numbers of paralysis and death in mice induced by ADP injection, but did not affect the bleeding time. Taken together, MP407 may be a potential candidate or lead compound for developing novel antiplatelet or antithrombotic agents for platelet hyperactivity-triggered disease therapy.
Subject(s)
Benzyl Compounds/pharmacology , Cyclic AMP/metabolism , Indoles/pharmacology , Platelet Aggregation/drug effects , Adenosine Diphosphate/adverse effects , Animals , Biological Transport/drug effects , Calcium/metabolism , Cell Adhesion Molecules/metabolism , Cyclic AMP/biosynthesis , Glycogen Synthase Kinase 3 beta/metabolism , Mice , Microfilament Proteins/metabolism , Phosphoproteins/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Thromboxane B2/biosynthesis , Tuberculosis, Pulmonary/chemically induced , Tuberculosis, Pulmonary/drug therapyABSTRACT
Infertility is a common condition. Because of traditional Chinese concepts that emphasize the importance of consanguinity, infertility has been a problem long recognized in Chinese history. The subject of infertility was addressed in the I-Jing, written some 3,000 years ago. The Nei-Jing, written during China's Warring States Period, described the mechanisms of infertility. Afterward, the library of knowledge on infertility steadily grew and became more sophisticated. The causes of female infertility in Chinese medicine include congenital deformity, menstruation abnormalities, organ dysfunctions, disturbances in the Qi or blood, malfunctions in the Chong or Ren meridians, emotional effects and the compression of concretions or conglomerations. Based on symptoms and mechanisms, female infertility can be classified into five patterns, including congenital deformity, kidney vacuity, liver depression, phlegm-damp and blood stasis. Chinese medicinal therapies for female infertility include Chinese herb drugs with pattern identification, artificial menstruation cycle therapy, single formula therapy, combined Chinese and Western medicine therapy, acupuncture and moxibustion. The relatively large range of therapies, while a hallmark of Chinese medicine, also points up instabilities in treatment outcomes. Thus, determining the most effective therapy is the most important point of clinical studies.
